Lung cancer is the leading cause of cancer mortality in both men and women in the United States with cigarette smoking being the primary known risk factor and has a low survival rate in part because it typically is at an advanced stage when first detected and treated. Studies to improve post-diagnosis outcome of lung cancer through early detection by means of low-dose spiral coaxial tomography (CT) screening and surgical intervention are promising. However, because more than 90 million active or ex-smokers in the United States alone are candidates for screening the potential cost is very high and may be prohibitive. Additionally, CT screening studies completed thus far are associated with a high incidence of false positive findings which may lead to unnecessary follow-up diagnostic testing. Based on demographic criteria it is possible to identify a group of individuals for whom the 10 year risk for lung cancer is more than 20%. Even in a group as selected as this, subjecting all individuals to close monitoring is costly and is associated with risk of false positive results. In previous studies we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells (NBEC) of lung cancer cases compared to non-lung cancer controls. A Lung Cancer Risk Test (LCRT) was identified comprising transcript abundance measurement of 14 key antioxidant, DNA repair and transcription factor genes measured in NBEC sampled at the time of bronchoscopy. The test was discovered in a case control study comprising 49 subjects (25 cancer and 24 controls) and validated in a second case-control study comprising 40 subjects (20 cases and 20 controls). In these studies the test had ROC AUC of better than 0.84 and odds ratio of more than 20 for identifying individuals over the age of 50 with more than 20 pack years smoking history who have lung cancer. The Specific Aims of this GO grant are: Aim 1. Establish a prospective cohort nested case control study to test the validity of a lung cancer risk test (LCRT) comprising 14 genes measured in normal airway epithelial cells obtained at bronchoscopy. Enroll at least 1050 subjects over the age of 50 and with more than 20 pack year smoking history but without prevalence lung cancer which will result in identification of 15 incident lung cancer cases with eight randomly selected controls for each case. This study will have sufficient power (>80%) to test an Odds Ratio of greater than 5.0. Establish a plan and resources for long-term (10-20 years) sample storage and analysis and subject follow-up. Aim 2. Establish a bank of NBEC and corresponding blood samples from the subjects enrolled in Aim 1. RNA, protein, and cytology slides from NBEC and peripheral blood leukocyte RNA and DNA and frozen plasma from blood will be archived. A biomarker that identifies individuals within a demographically defined high risk group who will develop lung cancer will enable even more focused selection for closer monitoring and further reduction in risk of false positive findings. Further, if CT screening is validated, limiting screening to the individuals with the highest demographic and biological risk will markedly reduce cost of implementation. PUBLIC HEALTH RELEVANCE: Project Narrative this is a proposal to validate the accuracy of a multi-gene Lung Cancer Risk Test (LCRT). An accurate LCRT may be used to design more efficient lung cancer screening and/or chemoprevention studies by enabling enrollment of the highest risk individuals, resulting in lower false positives and lower trial costs. In addition, if and when a screening and/or chemoprevention method is validated, it may be used to identify the individuals most likely to benefit, resulting in lower cost and reduced likelihood of adverse events.